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Pre-clinical data suggest that combining imatinib with traditional cytotoxic chemotherapy may improve imatinib efficacy. We conducted a Phase I study of imatinib in combination with paclitaxel in patients with advanced or metastatic solid tumors.Patients were accrued to the study in a standard 3 + 3 design. Patients were restaged every two cycles, and those with stable disease (SD), or better, continued study treatment without interruption. Maximally tolerated doses (MTDs) and pharmacokinetic profiles of combination imatinib and paclitaxel were assessed.Fifty-eight patients were enrolled, including 40 in the Phase I dose escalation portion. Alternating dose escalation of imatinib and paclitaxel on a 28-day cycle resulted in MTDs of 800 mg imatinib daily, on days 1-4, 8-11, 15-18, and 22-25, and 100 mg/m(2) paclitaxel weekly, on days 3, 10, and 17. Two expansion cohorts, comprising 10 breast cancer patients and 8 patients with soft-tissue sarcomas, were enrolled at the MTDs. The most common adverse events were flu-like symptoms (64 %) and nausea/vomiting (71 %). The most common Grade 3/4 toxicities were neutropenia (26 %), flu-like symptoms (12 %), and pain (12 %). There were no relevant differences in the pharmacokinetic profiles of either drug when given in combination compared with alone. Thirty-eight subjects were evaluable for response, 18 (47.4 %) of whom experienced clinical benefit. Five patients (13.2 %) had a partial response (PR) and 13 patients (34.2 %) had SD; the average time to progression in those with clinical benefit was 17 weeks (range: 7-28 weeks).This combination of imatinib and paclitaxel was reasonably safe and tolerable, and demonstrated evidence of anti-tumor activity. Further exploration in disease-specific Phase II trials is warranted.

S-CKD602 is a pegylated liposomal formulation of CKD-602. This study is the first to evaluate the factors affecting the high interpatient variability in the pharmacokinetic disposition of S-CKD602. S-CKD602 was administered intravenously (i.v.) every 3 weeks as part of a phase I study. Pharmacokinetics studies of the liposomal encapsulated and released CKD-602 in plasma were performed. The pharmacokinetic variability of S-CKD602 is associated with both linear and nonlinear clearances. Patients > or =60 years of age have a 2.7-fold higher exposure of S-CKD602 as compared with patients

Squamous cell carcinoma of the head and neck (SCCHN) is one of the most common malignancies worldwide, with low 5-year survival rates. Current strategies that block epidermal growth factor receptor (EGFR) have limited effects when administered as single agents. Targeting EGFR via intratumoral administration of phosphorothioate-modified antisense oligonucleotides has antitumor efficacy in xenograft models of SCCHN. Because intratumoral delivery of therapeutic agents has limited clinical application, the present study was undertaken to examine the therapeutic mechanisms of systemically delivered phosphorothioate-modified EGFR antisense oligonucleotides alone, or in combination with docetaxel, in a SCCHN xenograft model. EGFR antisense oligonucleotides were administered at 5 mg/kg i.p. daily in athymic mice bearing 1483 human SCCHN xenografts alone or in combination with docetaxel at 2.5 mg/kg i.p. once a week for 4 weeks. Administration of EGFR antisense oligonucleotides in combination with docetaxel improved antitumor efficacy and resulted in lower expression levels of EGFR, fewer proliferating cells, and more apoptotic cells in the tumors compared with controls. Systemic administration of phosphorothioated EGFR antisense oligonucleotides for 30 days increased the retention of docetaxel in the tumor by approximately 4-fold compared with tumors treated with docetaxel alone or docetaxel and EGFR sense oligonucleotides (P < 0.05). Combination of EGFR antisense oligonucleotides with low doses of docetaxel has antitumor efficacy, and it may be an effective treatment strategy for SCCHN.

Endovascular lung perfusion (ELP) is a technique designed to deliver high doses of cisplatin via the pulmonary artery for the treatment of lung tumors. The purpose of the current study was to evaluate variables that affect adduct formation.Thirteen swine underwent ELP. The first group (n = 6) underwent infusion of 150 mg cisplatin diluted to 0.5 mg/mL via a balloon occlusion catheter in the left pulmonary artery. Uptake was compared with that seen with systemic infusion. A second group (n = 7) underwent bilateral sequential infusion of the left pulmonary artery, followed by the right. Cisplatin (150 mg) was infused at one of three concentrations: 1 mg/mL (n = 5 lungs), 0.67 mg/mL (n = 5 lungs), or 0.5 mg/mL (n = 4 lungs). The Pearson coefficient was used to correlate uptake with infusion time, infusate concentration, animal weight, and initial mean pulmonary artery pressure.In the first group, cisplatin uptake in the control lung was less than 8% of that in the study lung. Infusion times for both groups ranged from 3 minutes to 56 minutes. Increases in infusion time correlated with increased adduct levels (r = 0.831; P.0001). Mean uptake at concentrations of 0.5, 0.67, and 1 mg/mL were 25.79, 12.43, and 13.12 fmol/mug, respectively. There was no significant correlation between pulmonary adduct levels and infusate concentration (r = 0.106; P = .72). Animal weight and initial mean pulmonary artery pressure were not correlated with adduct formation.ELP with longer infusions of cisplatin may lead to greater adduct formation in pulmonary tissues. Changes in concentration of the infusate do not affect uptake of cisplatin. Hemodynamic parameters do not affect cisplatin uptake.

Isolated hepatic perfusion (IHP) with melphalan is an established approach for patients with unresectable metastatic liver lesions. This study determined the safety and maximum tolerated dose (MTD) of 5-FU with oxaliplatin via IHP.Standard 3 × 3 Phase I design. Subjects with unresectable isolated CRC liver metastases scheduled for HAI pump were eligible. IHP used fixed-dose oxaliplatin with escalating 5-FU doses. Toxicity (CTCAE v 4.0) and response (RECIST), progression-free survival, and overall survival (OS) were assessed. Systemic and IHP plasma PK of 5-FU, anabolites, and platinum were determined.All 12 patients had received ≥ 1 line of pre-IHP chemotherapy. There were 4 grade 3 serious adverse events (33.3 %) and 1 grade 4 event (8.3 %). Also, 2 dose-limiting toxicities occurred at DL2 at 300 mg/m(2), resulting in expansion of DL1 at 200 mg/m(2) 5-FU, the eventual MTD. At 6-month follow-up, 9 patients (82 %) demonstrated partial response, while 2 (18 %) exhibited stable disease. Also, 64 % of patients demonstrated a50 % decrease in CEA. The 1- and 2-year OS probabilities were 90.9 and 71.6 %, respectively, with median follow-up of 24 months. IHP exposures (AUC0-60 min) were 10.9 ± 4.5 μgPt h/mL, 49.3 ± 30.7 μg h/mL 5-FU (DL1), and 70.5 ± 35.5 μg h/mL 5-FU (DL2). Systemic exposure (AUC0-inf) relative to IHP exposure was negligible for both platinum (1.1 ± 1.5 %) and 5-FU (0.09 ± 0.10 %).The MTD for IHP was 200 mg/m(2) 5-FU with 40 mg/m(2) oxaliplatin. Systemic exposure to the agents was minimal during IHP. The response and survival observed warrants assessment in a larger phase II trial.

283 Background: IHP is a proven approach for regional delivery of chemotherapy in patients with unresectable ILM. This study sought to determine safety and MTD of administering 5FU in combination with fixed dose oxaliplatin via IHP. Methods: Prospective Phase I dose escalation with standard 3x3 dosing. Subjects with unresectable ILM from CRC scheduled to receive an HAI pump were eligible. IHP employed fixed dose oxaliplatin (previously established)with escalating doses of 5FU. 1 endpoint was to determine MTD for this combination. 2 endpoints were response to IHP alone, PFS, and OS for IHP + HAI-FUDR. Systemic and IHP plasma PK of 5FU, anabolites, total, and free platinum were determined by validated assays. Results: Between Aug 2007 - Mar 2011, 11 subjects were enrolled. All patients received at least one line of pre-IHP systemic chemotherapy. There were 4 Grade 3 SAE (36.3%) and no grade 4 events. 2 DLTs occurred in the second dose cohort of 300mg/m2. Dose escalation was terminated and 200mg/m2 5FU was determined to be the MTD. There was 1 DLT in the dose de-escalating phase of 200mg/m2. At first follow-up, 9 pts (82%) had a partial response, while 2 (18%) had stable disease. 64% of pts had a >50% decrease in CEA level. Actuarial 1 and 2 year survival was 100% and 75% respectively, with median follow-up of 23 mos. IHP exposures (AUC0-60min) were 10.9±4.5 µgPt·h/mL (platinum), 49.3±30.7 µg·h/mL 5FU (DL1) and 70.5±35.5 µg·h/mL 5FU (DL2). Free platinum represented 82±14% of total platinum. Systemic exposure (AUC0-inf) relative to IHP exposure was negligible for both total platinum (1.1±1.5%) and 5FU (0.09±0.10%). IHP exposure to metabolites relative to 5FU was 4.9±2.5% for FUrd and 0.23±0.14% for FdUrd, respectively. Conclusions: MTD for IHP with 5FU and oxaliplatin is 200 mg/m2 and 40mg/m2 respectively. Systemic exposure to the agents was minimal. The response and survival observed in this dose escalation study warrants assessment in a larger phase II trial. [Table: see text]

7516 Background: IPI-504, a water-soluble analog of 17-allylamino-17-demethoxygeldanamycin (17-AAG), is an intravenously (IV) administered heat shock protein 90 (Hsp90) inhibitor that causes degrad...

2546 Background: A phase I clinical trial was conducted to determine the maximum-tolerated dose (MTD) of docetaxel (Doc) and oxaliplatin (Ox) in pts with advanced solid tumors. As part of this phas...

18142 Background: We have previously reported that docetaxel (Doc) demonstrates longer G2/M arrest and better synergistic effects with irradiation when compared with paclitaxel in human lung cancer cell lines. We designed a phase II clinical study targeting micrometastasis using upfront induction chemotherapy (CT) with Doc/cisplatin (CP) followed by sensitizing Doc chemoradiation (CRT) for patients (pts) with stage III NSCLC. Methods: Pts with inoperable stage III NSCLC were eligible. Induction CT consisted of Doc 75 mg/m2 and CP 75 mg/m2 on d 1 followed by rhG-CSF (150 ug/m2 sq on d 2 to 10). The CRT consisted of sensitizing Doc 12 mg/m2 twice per wk with daily RT (64.8 Gy to gross tumors and 45–57.6 Gy to subclinical disease). PK studies of Doc were performed during CT and CRT in each pt. The clearance (CL) and area under the plasma concentration versus time curve (AUC) were estimated. Results: 26 pts were enrolled and 16 completed study. Overall response rate was 69% [50% (8/16) PR and19% (3/16) CR]. 2-year survival was 57 %. During induction CT, primary grade (G) 3 toxicities were allergic reaction (10%), non-neutropenic infection (20%), nausea/vomiting (N/V) (10%), fatigue (10%), hypertension (5%) hyperglycemia (5%), dyspnea (5%) & fatigue (5%). There was no G3/4 hematologic toxicity. During CRT, 50% (4/8) of pts developed G3 esophagitis after Doc at 12 mg/m2. The next 8 pts received Doc at 10 mg/m2 with only 1 pt developing G3 esophagitis. Other G3 toxicities from CRT were N/V (28%), fatigue (14%), loss of appetite (14%), flushing (7%), chest pain (7%), & diarrhea (7%). No G3 or 4 pneumonitis or any G4 toxicity. Mean ± SD Doc CL at 75 and 10 mg/m2 were 20 ± 5 and 22 ± 10 L/h/m2, respectively. Ratio of Doc CL at 75 to 10 mg/m2 within a pt was 1.0 ± 0.4. Doc AUC at 75 and 10 mg/m2 were 3,933 ± 1,028 and 566 ± 257ng/ml·h, respectively. Conclusions: One-cycle full- dose Doc/CP with rhG-CSF followed by pulsed low-dose Doc CRT is associated with promising antitumor activity and low hematologic toxicity. Grade 3 esophagitis was associated with dose intensity of radiosensitizing Doc, and was minimized by dose reduction. Results suggest that this regimen should be further evaluated in pts with NSCLC. The PK disposition of Doc was similar at 75 and 10 mg/m2. No significant financial relationships to disclose.

2528 Background: STEALTH liposomes (SL), which contain lipids conjugated to polyethylene glycol (PEG), prolong the circulation time of a drug in plasma, achieve high and extended drug exposure in tumor, and are eliminated via the reticuloendothelial system (RES). S- CKD602 is a SL formulation of CKD-602, a camptothecin analogue. CKD-602 released from S-CKD602 is eliminated by the kidney. There is significant interpatient variability in the pharmacokinetic (PK) disposition of S-CKD602. Thus, there is a need to identify factors associated with the PK variability. We hypothesize that older patients (pts) have a reduced capacity to eliminate SL agents due to age-related impairment of the RES and that body composition alters the disposition of SL. Methods: PK studies of S-CKD602 were performed in a phase I study of S-CKD602 at 0.1 to 2.5 mg/m2 IV q 21 d in pts with solid tumors. Concentrations of encapsulated (E), released (R), and sum total (E + R) CKD-602 in plasma and CKD-602 in urine were measured by LC-MS/MS. Area under the plasma concentration versus time curve (AUC) was calculated and normalized by dose (AUC/dose). The ratio of total body weight to ideal body weight (TBW/IBW) was calculated as a measure of body composition. Results: Mean ± SD S-CKD602 sum total AUC/dose in pts < 60 (n = 13) and = 60 (n = 17) years of age (yo) were 4.5 ± 5.0 and 11.2 ± 11.0 (μg/ml·h)/(mg/m2), respectively (P No significant financial relationships to disclose.

2576 Background: STEALTH liposomal CKD-602 (S-CKD602), a camptothecin analogue, is eliminated by the reticuloendothelial system (RES), which consists of cells including monocytes. CKD-602 released from S-CKD602 is eliminated by the kidney. Therefore, we evaluated the PD relationship between monocyte and absolute neutrophil counts (ANC; as a control) in blood and S-CKD602 and non-liposomal CKD-602 (NL-CKD602) in patients (pts) with refractory solid tumors. We also evaluated the effect of age on these relationships. Methods: In a phase I study, S-CKD602 was administered IV x 1 q 3 wk at 0.1 to 2.5 mg/m2. In phase I and II studies, NL-CKD602 was administered IV qdx5d q 3 wk at 0.5 to 0.9 mg/m2/d and 0.5 mg/m2/d, respectively. The % decreases in ANC and monocytes at nadir were calculated. For S-CKD602, pharmacokinetic studies of encapsulated (E), released (R), and sum total (ST=E+R) CKD-602 in plasma and ST in urine were performed and measured by LC-MS/MS. Area under the plasma concentration versus time curve (AUC) was calculated. Results: For S-CKD602 in all pts (n = 27), the % decrease in ANC and monocytes were 42 ± 30 % and 58 ± 34 %, respectively (P = 0.003). For S-CKD602 in pts < 60 years old (yo) (n = 12), the % decrease in ANC and monocytes were 43 ± 31% and 58 ± 26 %, respectively (P = 0.001). For S-CKD602 in pts = 60 yo (n = 15), the % decrease in ANC and monocytes were 41 ± 31% and 45 ± 36 %, respectively (P = 0.50). For NL-CKD602 (n = 42), % decrease in ANC and monocytes were similar (P > 0.05). For S-CKD602, the relationship between % decrease in monocytes and released CKD-602 AUC in plasma in pts < 60 yo (R2 = 0.54) and = 60 yo (R2 = 0.49) was similar. For S-CKD602, the relationship between the % decrease in monocytes and the amount of CKD-602 recovered in the urine was stronger in pts < 60 yo (R2 = 0.82) compared with = 60 yo (R2 = 0.30). Conclusions: Monocytes are more sensitive to S-CKD602 compared with neutrophils and the increased sensitivity is related to the liposomal formulation and not CKD-602. These results suggest that monocytes engulf S-CKD602 which causes the release of CKD-602 from the liposome and toxicity to the monocytes, and that the effects are more prominent in pts < 60 yo. [Table: see text]

2013 Background: S-CKD602 is a pegylated STEALTH liposomal formulation of CKD-602, a semi-synthetic analogue of camptothecin (CPT) and topoisomerase I inhibitor. Preclinical studies have shown that prolonged exposure to CPT achieves the greatest antitumor activity. STEALTH liposomes prolong the circulation time in plasma, achieve high and extended drug exposure in tumor, and provide a convenient dosing schedule. Methods: Patients (pts) were administered S-CKD602 IV over 1 h once every 3 wks. Modified Fibonacci escalation was used (3–6 pts/cohort), and dose levels ranged from 0.1–2.5 mg/m2. Serial plasma samples were obtained prior to administration to 96 h after administration, and on days 8 and 15 of cycle 1. Plasma samples were processed to measure concentrations of encapsulated (E), released (R), and sum total (E+R) CKD602 total (lactone + hydroxyl acid) by LC-MS/MS. Area under the plasma conc versus time curve (AUC0-∞) and t1/2 were estimated. Results: 45 pts (21 male) have been treated: median age 62 y (range: 33–79 y); ECOG status: 0 and 1 (43 pts), 2 (2 pts). The majority of reported adverse events were grade (G) 1 and 2. Frequent nonhematological toxicities were asthenia, nausea, diarrhea, vomiting, and anorexia. Dose-limiting toxicities of G3 mucositis occurred in 1/6 pts at 0.3 mg/m2, G3/4 bone marrow suppression in 2/3 pts at 2.5 mg/m2, and G3 febrile neutropenia in 1/6 pts at 2.1 mg/m2. The maximum tolerated dose was 2.1 mg/m2. Stable disease for ≥ 6 cycles occurred in 5 pts (hepatocellular carcinoma (CA), thyroid, prostate, 2 pts sarcoma). Partial responses occurred in 2 pts with ovarian CA (1.7 and 2.1 mg/m2). At 2.1 mg/m2, the mean ± SD AUC and t1/2 of sum total S-CKD602 were 44 ± 33 μg/mL·h and 18 ± 8 h, respectively. In all plasma samples, >90% of drug was encapsulated. Conclusions: S-CKD602 represents a promising new STEALTH liposomal CPT agent with manageable toxicity and promising antitumor activity. Phase II studies of S-CKD602 at 2.1 mg/m2 IV once every 3 wks are planned. Prolonged plasma exposure over 1 to 2 wks is consistent with STEALTH liposomes and provides extended exposure compared with non-liposomal CPT. (Supported by ALZA and NIH/NCCR/GCRC #5M01 RR 00056). [Table: see text]